Identification of miRNAs Associated With Gender Difference in Osteoarthritis Patients (MIRGOA)

May 29, 2024 updated by: Istituto Ortopedico Rizzoli
The biological study involves the collection of samples from male and female patients (intraoperative waste tissue, blood and synovial fluid), suffering from mild and moderate-severe OA, who undergo endo or arthro-prosthesis surgery, or arthroplasty, for the identification and characterization of a panel of "gender-specific" miRNAs. MicroRNAs will be extracted from the samples (chondrocytes, synoviocytes, osteoblasts and plasma) and will be molecularly characterized in order to identify a panel of miRNAs differently expressed according to the gender and severity of OA. The lymphocyte and phenotypically and functionally characterized populations will be isolated from the corpuscular component and the synovial fluid, in order to evaluate a possible gender-specific difference in the progression of OA-dependent inflammation.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Osteoarthritis (OA) is a chronic degenerative joint disease of considerable socio-economic impact, of which a primary and a secondary form are distinguished. Primary OA is a mild form that occurs mainly in the joints of the hands, feet, knee, and hip, and appears in young subjects. Secondary OA derives from different factors that modify the microenvironment of the cartilage such as trauma, congenital joint deformities, metabolic defects, infections that cause post-infectious arthritis, endocrine and neuropathic diseases and disorders that alter the normal structure and function of hyaline cartilage (eg . rheumatoid arthritis, gout, chondrocalcinosis), and is more prevalent in old age.

As regards the secondary form of OA, correlated with advancing age due to the natural aging process of the joint and to events of a traumatic nature, it is hypothesized that a key role in the etiology and progression of the disease may be played by the genre. Immune responses are known to differ in males and females. Some meta-analyzes reveal how the presence of some polymorphisms (ADAM12) in male patients predispose to the development of OA more than in women, especially in the knee joint. Furthermore, new molecular evidence suggests that in patients with OA there is a gender-specific activation of PI3K-AKT and hypoxia signaling, suggesting the presence of possible gender-specific protein factors that may modulate bone metabolism and disease progression. In this regard, studies evaluating the responses of joint chondrocytes to systemic factors suggest that there are differences in the biochemical and molecular characteristics of male and female cells, without prejudice to the fundamental role of hormones in the different gender-specific response to the development and progression of pathology.

It is widely known that the regulation of bone remodeling processes is entrusted to a hormonal mechanism, which mainly involves parathyroid hormone, vitamin D and calcitonin. Other hormone regulators involved are sex hormones (estrogen, testosterone), thyroid hormones, corticosteroids (including cortisone), insulin, and growth factors (including growth hormone).

In the development of OA it is thought that sex hormones may act in a prevalent way. In women of childbearing age, estrogen has a protective action on the bone, inhibiting bone remodeling, especially bone resorption; while in the post-menopausal period, circulating estrogens are reduced compared to testosterone, strongly contributing to an imbalance in bone remodeling, favoring the stiffening of the subchondral bone and the development of osteophytes at the joint margins. The osteophytes seem to be developed in an attempt to stabilize the joint damage. Consequently, the synovial membrane becomes inflamed and thickened, producing synovial fluid with less viscosity and in greater quantities and favoring the development of an inflammatory process on site. Obviously, the entire joint will be damaged up to the reduction of joint mobility and ankylosis.

Similarly men, even if they do not undergo a real andropause, starting from 45 years of age they suffer a progressive decline in the production and release of testosterone, whose levels after the age of 65 are no longer sufficient to maintain good efficiency of the bone tissue favoring its resorption and the possible onset of the pathology. However, it is not known whether the potential differences related to gender, in terms of hormonal release and alteration of bone homeostasis, may be related to the severity of the disease, that is to the development of the inflammatory condition associated with it.

It is therefore necessary to highlight another characteristic of OA, both in terms of development and progression, namely the different inflammatory response based on the patient's gender. In OA, as with other inflammatory diseases, the response of the male immune system induced by inflammation of the synovium and synovial fluid is different than in the female counterpart, suggesting that there could be differences between the two sexes in the levels of immunomodulators in joint tissues, including the synovial membrane, synovial fluid and cartilage itself. Recent studies attribute to the inflammatory microenvironment a key role in the prognosis of the disease.

Recently, the investigators obtained evidences regarding the role of microRNAs and lncRNAs as biomarkers of bone regeneration, directly involving specific cellular signalings (hypoxia, epithelium-mesenchyma transition and mechano-transduction), and representing, in some cases, a crucial point for the development of orthopedic diseases, such as osteoporosis, OA and forms of degeneration of the intervertebral discs. From an ongoing screening on tissue (joint) miRNA and lncRNA differently expressed and which could play a key role in the process of osseointegration of the prosthetic implant, miR-31-5p, miR-33a-5p, miR-133a, miR-675-5p and lncH19 were also evaluated. The correlation analysis between their expression profile and the patient's gender show a different expression of some of them and a gender-specific response on target genes and signaling.

The hypothesis of the study is that there are gender differences that contribute to the increase in the incidence and severity of OA, both in molecular terms (qualitative and quantitative differences in miRNAs involved in transcriptional and translational gene regulation) and inflammatory, such as differences in the development and progression of the lymphocyte population, involved in the OA-related inflammatory response. Therefore, the study aims to identify, characterize and evaluate an expression panel of tissue and circulating miRNAs isolated from patients with both mild and moderate-severe OA, who undergo prosthetic surgery, so as to be able to define possible gender-specific biomarkers of disease progression useful for controlling the osteointegration process of the prosthetic implant, and to be correlated with the pre- and post-operative inflammatory response.

The biological study involves the collection of samples from patients of both sexes suffering from OA, be it mild or moderate-severe, who undergo endo or arthro-prosthesis surgery, or arthroscopy. In particular, the following samples will be collected: 1) cells, such as synoviocytes, osteoblasts and chondrocytes deriving from operating waste tissues; 2) synovial fluid isolated during the operation; and 3) peripheral blood, from which to isolate the plasma and the lymphocyte component, taken 24 hours before surgery, and 72 hours and 1 month after surgery.

The miRNAs will be isolated from the samples isolated from tissues and plasma and will be molecularly characterized in order to identify a panel (also built starting from information obtained from the literature) expressed on the basis of the gender and severity of OA. The identified miRNAs will be validated, in vitro, using a specific molecular approach. The lymphocyte component of the blood and, isolated by means of special separation protocols through cell-specific magnetic beads, will be phenotypically characterized by a flow cytometric approach. The lymphocyte populations that will show a different phenotype between the male and female gender in correlation with the aggressiveness of the disease, will be analyzed and monitored over time up to 1 month of follow-up together with the analysis of synovial fluids, through in vitro studies of cytokine release and ELISA assays.

Study Type

Observational

Enrollment (Estimated)

20

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
    • Palermo
      • Bagheria, Palermo, Italy, 90011
        • Recruiting
        • Dipartimento Rizzoli Sicilia - Istituto Ortopedico Rizzoli
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

A maximum number of n = 20 patients with clinical and radiological diagnosis of OA will be enrolled: n = 10 with OA defined as "moderate-severe" equivalent to the KL score greater than or equal to grade III (n = 5 males and n = 5 females); and n = 10 with OA defined as "mild" equivalent to the grade I and II KL score (n = 5 males and n = 5 females), who undergo endo or arthro-prosthesis surgery, or arthroscopy. All patients will be enrolled in the clinical trial only after having personally dated and signed the written informed consent.

Description

Inclusion Criteria:

  • Patients of both sexes suffering from OA in hospital for the surgical treatment of OA (endo- or arthroplasty, or arthroscopy) with an interval of at least three months from any previous infiltrative treatment of any kind;
  • Patients with a Kellgren and Lawrence (KL) [Kohn 2016] score greater than or equal to grade III will be enrolled in the 'Moderate-severe OA' group and those with grade I and II KL scores in the 'MIld OA' group;
  • Patients able to provide the list of medications and supplements taken;
  • Patients able to provide informed consent to treatment.

Exclusion Criteria:

  • Patients who have undergone previous joint surgery or who have excessive joint deformity.
  • Patients with recent trauma, osteonecrosis or OA induced by previous or current joint infection;
  • Patients with metabolic pathologies;
  • Patients with previous or current oncological pathologies;
  • Women in a climacteric (date of last menstruation less than one year);
  • Patients with severe cognitive deficits or psychiatric disorders;
  • Autoimmune diseases (eg rheumatoid arthritis).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change assessment of OA 'gender-specific miRNA panel during time
Time Frame: Time points: 24 hours; 72 hours; 1 month

Identification and characterization of a 'gender-specific' miRNA panel related to disease progression in patients with mild OA (OA with Kellgren Lawrence-KL grade I and II) and moderate-severe (OA with greater or greater KL score equal to grade III).

The miRNAs will be isolated from patients affected by OA who undergo endo- or arthro-prosthesis operations starting: 1) from cells isolated from waste tissues; and 2) from the plasma taken 24 hours before surgery, and subsequently at 72 hours and 1 month from this.
Time points: 24 hours; 72 hours; 1 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Functional role of OA 'gender-specific' miRNAs
Time Frame: 2 months
Define the functional role (regulated or modulated signaling) of each deregulated (up or down-regulated) miRNA through specific in vitro studies.
2 months
Change assessment of OA 'gender-specific' inflammatory response during time
Time Frame: Time points: 24 hours; 72 hours; 1 month
Characterize any differences in the inflammatory response (release of cytokines and inflammatory factors) based on the patient's gender and the severity of the disease, analyzing the lymphocyte component isolated from the blood sample performed 24h before and 72h and 1 month after surgery and analyzing the liquid synovial isolated in the operative site.
Time points: 24 hours; 72 hours; 1 month
OA 'gender-specific' miRNAs as biomarkers of osteointegration
Time Frame: 12 months
Define some miRNAs (modulated in the same way at the tissue and circulating level) that can be used as "gender-specific" predictive biomarkers of the efficiency of the osteointegrative capacity in the patient with OA.
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Istituto Ortopedico Rizzoli

Investigators

  • Principal Investigator: Viviana Costa, B.Sc Ph.D, IRCCS Istituto Ortopedico Rizzoli

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 21, 2022

Primary Completion (Estimated)

July 31, 2024

Study Completion (Estimated)

July 31, 2024

Study Registration Dates

First Submitted

April 13, 2021

First Submitted That Met QC Criteria

April 19, 2021

First Posted (Actual)

April 20, 2021

Study Record Updates

Last Update Posted (Actual)

May 30, 2024

Last Update Submitted That Met QC Criteria

May 29, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 148/2021/Sper/IOR

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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